The overall goal of this project is to utilize immunologic, molecular, and synthetic approaches to develop means for controlling and treating human cytomegalovirus (CMV) infections. The specific approaches to be employed include: 1) Generation of human monoclonal antibodies (HMabs) to CMV, particularly to CMV antigens that are expressed on infected cell surface. 2) Detailed studies will be performed on the interactions between susceptible cells and viral envelope glycoproteins as identified and isolated by these HMabs using immunoaffinity chromatography. 3) Production and functional characterization of immunoconjugates with different classes of reagents (selective complement activators, toxins, and anti-viral drugs) for selective targeting and destruction of infected cells expressing CMV antigens. The project involves scientists at three institutions and takes advantage of the special areas of expertise and technical resources already well established in the respective laboratories. These approaches are dependent on production of HMabs to CMV. While impaired cellular immunity is thought to be the major contributing factor in immunocompromised patients, administration of human plasma with high anti-CMV titers modifies the severity or eliminates CMV infections. The known mechanisms where by antibodies to CMV can modulate infection include neutralization of extracellular virus, complement- mediated lysis of CMV-infected neutralization of extracellular virus, complement-mediated lysis of CMV-infected cells and cell- mediated immunity by antibody-dependent cellular cytotoxicity. To begin these studies three IgG neutralizing HMabs to CMV have already been produced using human somatic cell hybridization techniques. The successful production of HMabs to CMV should eventually replace human plasma as a potentially unlimited and safe source of antibodies in the prevention of CMV infections. Their use as targeting moieties to facilitate the selective delivery of toxins of antiviral drugs to infected cells will provide a new approach to the treatment of CMV infections.